Date of Award

2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biotechnology Science and Engineering

Committee Chair

Robert McFeeters

Committee Member

Emanuel Waddell

Committee Member

Luis R. Cruz-Vera

Committee Member

Joseph Ng

Committee Member

Roy Magnuson

Subject(s)

Antibiotics--Biotechnology., Enzyme kinetics., Enzyme inhibitors., Drug resistance in microorganisms., Hydrolases.

Abstract

Antibiotic resistant bacterial infections have become increasingly difficult to treat resulting in approximately 23,000 deaths per year in the U.S. alone. Some bacterial infections, like P. aeruginosa and M. tuberculosis, have become pan- and multi-drug resistance further limiting treatment options. This has placed an increased demand on the medical community to find novel antibiotics and novel antibiotic drug targets that can be used for narrow spectrum inhibition of bacteria. One such target is bacterial peptidyl- tRNA hydrolase 1 (Pth1). Pth1 recycles tRNA by hydrolyzing the bond between peptidyl-tRNA and the growing polypeptide chain during abortive translation, thus, allowing free tRNA to be recycled for future protein biosynthesis. Past studies have shown Pth1 to be essential to bacterial, but not eukaryotic, life. Where bacteria possess a single copy of Pth1 in their genome, eukaryotes have a multicomponent tRNA recycling system that is predicted to compensate for loss of Pth1 function. Likewise, several previous studies have provided valuable insight into Pth1 structure and dynamics. However, these studies were limited to single bacterial Pth1 homologs. In contrast, this study used multiple homologs across phylogenetic space to characterize the in vitro biochemical properties, kinetic properties, and inhibition profiles from different phylogenetic clades. This study established three distinct phylogenetic clades with their own unique characteristics. Importantly, this study also found that both narrow spectrum activity and small molecule inhibition was possible across phylogenetic space. Thus, this data further established the attractiveness of bacterial Pth1 as a novel drug target.

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